Polyphosphates and Complement Activation

Abstract

To sustain life in environments that are fraught with risks of life-threatening injury, organisms have developed innate protective strategies such that the response to wounds is rapid and localized, with the simultaneous recruitment of molecular, biochemical, and cellular pathways that limit bleeding and eliminate pathogens and damaged host cells, while promoting effective healing. These pathways are both coordinated and tightly regulated, as their over- or under-activation may lead to inadequate healing, disease, and/or demise of the host. Recent advances in our understanding of coagulation and complement, a key component of innate immunity, have revealed an intriguing linkage of the two systems. Cell-secreted polyphosphate promotes coagulation, while dampening complement activation, discoveries that are providing insights into disease mechanisms and suggesting novel therapeutic strategies.

Keywords: C1-esterase inhibitor; age-related macular degeneration; coagulation; inflammation; innate immunity; membrane attack complex; mouse models; thrombosis.

Figure 1

Schematic of complement activation pathways. Complement activation proceeds via the classical, lectin, or alternative pathways, triggered by exposure of surveillance molecules, C1q, MBL, collectins and ficolins, of specific danger signals. The alternative pathway is constitutively “on,” due to spontaneous hydrolysis of C3. The pathways converge to form C3 convertases: C4b2a for the classical and lectin pathways, C3bBb for the alternative pathway. C4a and C3a, are released with cleavage of C4 and C3, respectively. As C3b is further generated, C5 convertases C4bBbC3b and C3bBbC3b are formed, resulting in liberation of the most potent anaphylatoxin C5a, in conjunction with C5b. C5b is the initial component required for spontaneous assembly of the C5b-9 membrane attack complex (MAC) which polymerizes and induces lysis of the cellular target. MBL, mannose binding lectin, CRP, C-reactive protein, CHO, carbohydrate, MASP, MBL associated serine protease. Figure and legend from Conway (14).

Figure 2

Mechanisms by which polyP regulates complement activation. In resting platelets, polyP and C1-INH are housed in different organelles. After activation, polyP and C1-INH coalesce toward the center of the platelets where they colocalize and are subsequently secreted (66). PolyP triggers a conformational change in factor XII, resulting in generation of XIIa, which can activate prekallikrein (PK) and/or factor XI to XIa. Kallikrein (K) or plasmin (not shown) can further cleave XIIa to generate βXIIa which may activate C1r and thus promote complement activation. C1-INH dampens that pathway by inhibiting factor XII, XIIa, βXIIa, and kallikrein (K). C1s cleaves C4 and C2 to generate the C4b2a C3 convertase, which ultimately leads to formation of the C5b,6 complex, and assembly of the C5b-9 membrane attack complex (MAC). PolyP or heparin potentiate the inhibitory function of C1-INH via direct interactions with C1-INH and the target protease, C1s. PolyP also destabilizes C5b,6, thereby dampening formation of the MAC. Interestingly, in spite of binding to factors XIa and XIIa, reduced levels or function of C1-INH do not cause thrombosis, possibly due in part to differential effects of polyanions (polyP, heparin) on the function of the target enzymes. The over-riding effect of polyP in a serum-based endothelial cell culture system is to suppress complement activation. Figure and legend from Wijeyewickrema et al. (66).